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Analytical and Bioanalytical Chemistry

, Volume 407, Issue 8, pp 2107–2116 | Cite as

Distribution and quantification of irinotecan and its active metabolite SN-38 in colon cancer murine model systems using MALDI MSI

  • Achim Buck
  • Susanne Halbritter
  • Christoph Späth
  • Annette Feuchtinger
  • Michaela Aichler
  • Horst Zitzelsberger
  • Klaus-Peter Janssen
  • Axel WalchEmail author
Research Paper
Part of the following topical collections:
  1. Mass Spectrometry Imaging

Abstract

Tissue distribution and quantitative analysis of small molecules is a key to assess the mechanism of drug action and evaluate treatment efficacy. The prodrug irinotecan (CPT-11) is widely used for chemotherapeutic treatment of colorectal cancer. CPT-11 requires conversion into its active metabolite SN-38 to exert the desired pharmacological effect. MALDI-Fourier transform ion cyclotron resonance (FT-ICR) and MALDI-time-of-flight (TOF) mass spectrometry imaging (MSI) were performed for detection of CPT-11 and SN-38 in tissue sections from mice post CPT-11 injection. In-depth information was gained about the distribution and quantity of drug compounds in normal and tumor tissue. The prodrug was metabolized, as proven by the detection of SN-38 in liver, kidney and digestive tract. In tumors from genetic mouse models for colorectal cancer (Apc 1638N/wt x pvillin-Kras V12G ), CPT-11 was detected but not the active metabolite. In order to correlate drug distribution relative to vascularization, MALDI data were superimposed with CD31 (PECAM-1) immunohistochemistry. This analysis indicated that intratumoral access of CPT-11 mainly occurred by extravasation from microvessels. The present study exploits the power of MALDI MSI in drug analysis, and presents a novel approach to monitor drug distribution in relation to vessel functionality in preclinical and clinical research.

Keywords

Mass spectrometry MALDI imaging Drug monitoring/drug screening Irinotecan SN-38 

Notes

Acknowledgments

This work was supported by Ministry of Education and Research of the Federal Republic of Germany BMBF (No. 01ZX1310B and No. 01IB10004E), the Deutsche Forschungsgemeinschaft (SFB 824 TP Z2 and WA 1656/3-1, HO 1258/3-1), and Helmholtz Zentrum München (TKP-Project). The authors thank Ulrike Buchholz, Claudia-Mareike Pflüger, Gabriele Mettenleiter, and Andreas Voss for their excellent technical assistance.

Supplementary material

216_2014_8237_MOESM1_ESM.pdf (177 kb)
ESM 1 (PDF 176 kb)

References

  1. 1.
    Akhtar R, Chandel S, Sarotra P, Medhi B (2014) Current status of pharmacological treatment of colorectal cancer. World J Gastrointest Oncol 6(6):177–183. doi: 10.4251/wjgo.v6.i6.177 Google Scholar
  2. 2.
    Wang JC (2002) Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol 3(6):430–440. doi: 10.1038/nrm831 CrossRefGoogle Scholar
  3. 3.
    Champoux JJ (2001) DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem 70:369–413. doi: 10.1146/annurev.biochem.70.1.369 CrossRefGoogle Scholar
  4. 4.
    Satoh T, Hosokawa M, Atsumi R, Suzuki W, Hakusui H, Nagai E (1994) Metabolic activation of CPT-11, 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin, a novel antitumor agent, by carboxylesterase. Biol Pharm Bull 17(5):662–664CrossRefGoogle Scholar
  5. 5.
    Xu G, Zhang W, Ma MK, McLeod HL (2002) Human carboxylesterase 2 is commonly expressed in tumor tissue and is correlated with activation of irinotecan. Clin Cancer Res : Off J Am Assoc Cancer Res 8(8):2605–2611Google Scholar
  6. 6.
    Xie M, Yang D, Wu M, Xue B, Yan B (2003) Mouse liver and kidney carboxylesterase (M-LK) rapidly hydrolyzes antitumor prodrug irinotecan and the N-terminal three quarter sequence determines substrate selectivity. Drug Metab Dispos: Biol Fate Chem 31(1):21–27CrossRefGoogle Scholar
  7. 7.
    Senter PD, Beam KS, Mixan B, Wahl AF (2001) Identification and activities of human carboxylesterases for the activation of CPT-11, a clinically approved anticancer drug. Bioconjug Chem 12(6):1074–1080CrossRefGoogle Scholar
  8. 8.
    Kawato Y, Aonuma M, Hirota Y, Kuga H, Sato K (1991) Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 51(16):4187–4191Google Scholar
  9. 9.
    Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan study group. N Engl J Med 343(13):905–914. doi: 10.1056/NEJM200009283431302 CrossRefGoogle Scholar
  10. 10.
    Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355(9209):1041–1047CrossRefGoogle Scholar
  11. 11.
    Santos A, Zanetta S, Cresteil T, Deroussent A, Pein F, Raymond E, Vernillet L, Risse ML, Boige V, Gouyette A, Vassal G (2000) Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Clin Cancer Res: Off J Am Assoc Cancer Res 6(5):2012–2020Google Scholar
  12. 12.
    Dodds HM, Haaz MC, Riou JF, Robert J, Rivory LP (1998) Identification of a new metabolite of CPT-11 (irinotecan): pharmacological properties and activation to SN-38. J Pharmacol Exp Ther 286(1):578–583Google Scholar
  13. 13.
    Norris JL, Caprioli RM (2013) Analysis of tissue specimens by matrix-assisted laser desorption/ionization imaging mass spectrometry in biological and clinical research. Chem Rev 113(4):2309–2342. doi: 10.1021/cr3004295 CrossRefGoogle Scholar
  14. 14.
    Buck A, Walch A (2014) In situ drug and metabolite analyzes in biological and clinical research by MALDI MS imaging. Bioanalysis 6(9):1241–1253. doi: 10.4155/bio.14.88 CrossRefGoogle Scholar
  15. 15.
    Lewellen TK (2008) Recent developments in PET detector technology. Phys Med Biol 53(17):R287–R317. doi: 10.1088/0031-9155/53/17/R01 CrossRefGoogle Scholar
  16. 16.
    Zierhut ML, Yen YF, Chen AP, Bok R, Albers MJ, Zhang V, Tropp J, Park I, Vigneron DB, Kurhanewicz J, Hurd RE, Nelson SJ (2010) Kinetic modeling of hyperpolarized 13C1-pyruvate metabolism in normal rats and TRAMP mice. J Magn Reson 202(1):85–92. doi: 10.1016/j.jmr.2009.10.003 CrossRefGoogle Scholar
  17. 17.
    Stoeckli M, Staab D, Schweitzer A (2007) Compound and metabolite distribution measured by MALDI mass spectrometric imaging in whole-body tissue sections. Int J Mass Spectrom 260(2–3):195–202. doi: 10.1016/j.ijms.2006.10.007 CrossRefGoogle Scholar
  18. 18.
    Hopfgartner G, Varesio E, Stoeckli M (2009) Matrix-assisted laser desorption/ionization mass spectrometric imaging of complete rat sections using a triple quadrupole linear ion trap. Rapid Commun Mass Spectrom 23(6):733–736. doi: 10.1002/Rcm.3934 CrossRefGoogle Scholar
  19. 19.
    Pirman DA, Yost RA (2011) Quantitative tandem mass spectrometric imaging of endogenous acetyl-L-carnitine from piglet brain tissue using an internal standard. Anal Chem 83(22):8575–8581. doi: 10.1021/ac201949b CrossRefGoogle Scholar
  20. 20.
    Shahidi-Latham SK, Dutta SM, Prieto Conaway MC, Rudewicz PJ (2012) Evaluation of an accurate mass approach for the simultaneous detection of drug and metabolite distributions via whole-body mass spectrometric imaging. Anal Chem 84(16):7158–7165. doi: 10.1021/ac3015142 CrossRefGoogle Scholar
  21. 21.
    Jirasko R, Holcapek M, Kunes M, Svatos A (2014) Distribution study of atorvastatin and its metabolites in rat tissues using combined information from UHPLC/MS and MALDI-Orbitrap-MS imaging. Anal Bioanal Chem. doi: 10.1007/s00216-014-7880-y Google Scholar
  22. 22.
    Takai N, Tanaka Y, Saji H (2014) Quantification of small molecule drugs in biological tissue sections by imaging mass spectrometry using surrogate tissue-based calibration standards. Mass Spectrom 3(1):A0025. doi: 10.5702/massspectrometry.A0025 CrossRefGoogle Scholar
  23. 23.
    Kim YH, Fujimura Y, Hagihara T, Sasaki M, Yukihira D, Nagao T, Miura D, Yamaguchi S, Saito K, Tanaka H, Wariishi H, Yamada K, Tachibana H (2013) In situ label-free imaging for visualizing the biotransformation of a bioactive polyphenol. Sci Rep 3:2805. doi: 10.1038/srep02805 Google Scholar
  24. 24.
    Groseclose MR, Castellino S (2013) A mimetic tissue model for the quantification of drug distributions by MALDI imaging mass spectrometry. Anal Chem. doi: 10.1021/ac400892z Google Scholar
  25. 25.
    Liu X, Ide JL, Norton I, Marchionni MA, Ebling MC, Wang LY, Davis E, Sauvageot CM, Kesari S, Kellersberger KA, Easterling ML, Santagata S, Stuart DD, Alberta J, Agar JN, Stiles CD, Agar NY (2013) Molecular imaging of drug transit through the blood-brain barrier with MALDI mass spectrometry imaging. Sci Rep 3:2859. doi: 10.1038/srep02859 Google Scholar
  26. 26.
    Castellino S, Groseclose MR, Sigafoos J, Wagner D, de Serres M, Polli JW, Romach E, Myer J, Hamilton B (2013) Central nervous system disposition and metabolism of Fosdevirine (GSK2248761), a non-nucleoside reverse transcriptase inhibitor: an LC-MS and matrix-assisted laser desorption/ionization imaging MS investigation into central nervous system toxicity. Chem Res Toxicol 26(2):241–251. doi: 10.1021/tx3004196 CrossRefGoogle Scholar
  27. 27.
    Janssen KP, Alberici P, Fsihi H, Gaspar C, Breukel C, Franken P, Rosty C, Abal M, El Marjou F, Smits R, Louvard D, Fodde R, Robine S (2006) APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology 131(4):1096–1109. doi: 10.1053/j.gastro.2006.08.011 CrossRefGoogle Scholar
  28. 28.
    Strohalm M, Kavan D, Novak P, Volny M, Havlicek V (2010) mMass 3: a cross-platform software environment for precise analysis of mass spectrometric data. Anal Chem 82(11):4648–4651. doi: 10.1021/ac100818g CrossRefGoogle Scholar
  29. 29.
    Huber K, Aichler M, Sun N, Buck A, Li Z, Fernandez IE, Hauck SM, Zitzelsberger H, Eickelberg O, Janssen KP, Keller U, Walch A (2014) A rapid ex vivo tissue model for optimising drug detection and ionisation in MALDI imaging studies. Histochem Cell Biol. doi: 10.1007/s00418-014-1223-0 Google Scholar
  30. 30.
    Zhu HJ, Appel DI, Jiang Y, Markowitz JS (2009) Age- and sex-related expression and activity of carboxylesterase 1 and 2 in mouse and human liver. Drug Metab Dispos: Biological Fate Chem 37(9):1819–1825. doi: 10.1124/dmd.109.028209 CrossRefGoogle Scholar
  31. 31.
    Yasunaga M, Furuta M, Ogata K, Koga Y, Yamamoto Y, Takigahira M, Matsumura Y (2013) The significance of microscopic mass spectrometry with high resolution in the visualisation of drug distribution. Sci Rep 3:3050. doi: 10.1038/srep03050 CrossRefGoogle Scholar
  32. 32.
    Pardridge WM (2011) Drug transport in brain via the cerebrospinal fluid. Fluids Barriers CNS 8(1):7. doi: 10.1186/2045-8118-8-7 CrossRefGoogle Scholar
  33. 33.
    Blaney SM, Takimoto C, Murry DJ, Kuttesch N, McCully C, Cole DE, Godwin K, Balis FM (1998) Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates. Cancer Chemother Pharmacol 41(6):464–468. doi: 10.1007/s002800050768 CrossRefGoogle Scholar
  34. 34.
    Xu T, Chen J, Lu Y, Wolff JE (2010) Effects of bevacizumab plus irinotecan on response and survival in patients with recurrent malignant glioma: a systematic review and survival-gain analysis. BMC Cancer 10:252. doi: 10.1186/1471-2407-10-252 CrossRefGoogle Scholar
  35. 35.
    Vredenburgh JJ, Desjardins A, Reardon DA, Friedman HS (2009) Experience with irinotecan for the treatment of malignant glioma. Neuro Oncol 11(1):80–91. doi: 10.1215/15228517-2008-075 CrossRefGoogle Scholar
  36. 36.
    Gerstner ER, Duda DG, di Tomaso E, Ryg PA, Loeffler JS, Sorensen AG, Ivy P, Jain RK, Batchelor TT (2009) VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer. Nat Rev Clin Oncol 6(4):229–236. doi: 10.1038/nrclinonc.2009.14 CrossRefGoogle Scholar
  37. 37.
    Kawamura K, Hashimoto H, Ogawa M, Yui J, Wakizaka H, Yamasaki T, Hatori A, Xie L, Kumata K, Fujinaga M, Zhang MR (2013) Synthesis, metabolite analysis, and in vivo evaluation of [(11)C]irinotecan as a novel positron emission tomography (PET) probe. Nucl Med Biol 40(5):651–657. doi: 10.1016/j.nucmedbio.2013.03.004 CrossRefGoogle Scholar
  38. 38.
    Guichard S, Terret C, Hennebelle I, Lochon I, Chevreau P, Fretigny E, Selves J, Chatelut E, Bugat R, Canal P (1999) CPT-11 converting carboxylesterase and topoisomerase activities in tumour and normal colon and liver tissues. Br J Cancer 80(3–4):364–370. doi: 10.1038/sj.bjc.6690364 CrossRefGoogle Scholar
  39. 39.
    Gupta E, Lestingi TM, Mick R, Ramirez J, Vokes EE, Ratain MJ (1994) Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res 54(14):3723–3725Google Scholar
  40. 40.
    Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6(8):583–592. doi: 10.1038/nrc1893 CrossRefGoogle Scholar
  41. 41.
    Nilsson A, Fehniger TE, Gustavsson L, Andersson M, Kenne K, Marko-Varga G, Andren PE (2010) Fine mapping the spatial distribution and concentration of unlabeled drugs within tissue micro-compartments using imaging mass spectrometry. PLoS One 5(7):e11411. doi: 10.1371/journal.pone.0011411 CrossRefGoogle Scholar
  42. 42.
    Morosi L, Spinelli P, Zucchetti M, Pretto F, Carra A, D’Incalci M, Giavazzi R, Davoli E (2013) Determination of paclitaxel distribution in solid tumors by nano-particle assisted laser desorption ionization mass spectrometry imaging. PLoS One 8(8):e72532. doi: 10.1371/journal.pone.0072532 CrossRefGoogle Scholar
  43. 43.
    Pirman DA, Reich RF, Kiss A, Heeren RM, Yost RA (2013) Quantitative MALDI tandem mass spectrometric imaging of cocaine from brain tissue with a deuterated internal standard. Anal Chem 85(2):1081–1089. doi: 10.1021/ac302960j CrossRefGoogle Scholar
  44. 44.
    Mollica A, Stefanucci A, Feliciani F, Cacciatore I, Cornacchia C, Pinnen F (2012) Delivery methods of camptothecin and its hydrosoluble analogue irinotecan for treatment of colorectal cancer. Curr Drug Deliv 9(2):122–131CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Achim Buck
    • 1
  • Susanne Halbritter
    • 1
  • Christoph Späth
    • 3
  • Annette Feuchtinger
    • 1
  • Michaela Aichler
    • 1
  • Horst Zitzelsberger
    • 2
  • Klaus-Peter Janssen
    • 3
  • Axel Walch
    • 1
    Email author
  1. 1.Research Unit Analytical Pathology, Institute of Pathology, Helmholtz Zentrum MünchenGerman Research Center for Environmental HealthNeuherbergGermany
  2. 2.Research Unit Radiation Cytogenetics, Helmholtz Zentrum MünchenGerman Research Center for Environmental HealthNeuherbergGermany
  3. 3.Department of Surgery, Klinikum rechts der IsarTechnische Universität MünchenMunichGermany

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